In 1755 LeRoy passed the discharge of a Leyden jar through the orbit of a man who was blind from cataract and the patient saw “flames passing rapidly downwards.” Ever since, there has been a fascination with electrically elicited visual perception. The general concept of electrical stimulation of retinal cells to produce these flashes of light or phosphenes has been known for quite some time. Based on these general principles, some early attempts at devising a prosthesis for aiding the visually impaired have included attaching electrodes to the head or eyelids of patients. While some of these early attempts met with some limited success, these early prosthetic devices were large, bulky and could not produce adequate simulated vision to truly aid the visually impaired.
In the early 1930's, Foerster investigated the effect of electrically stimulating the exposed occipital pole of one cerebral hemisphere. He found that, when a point at the extreme occipital pole was stimulated, the patient perceived a small spot of light directly in front and motionless (a phosphene). Subsequently, Brindley and Lewin (1968) thoroughly studied electrical stimulation of the human occipital (visual) cortex. By varying the stimulation parameters, these investigators described in detail the location of the phosphenes produced relative to the specific region of the occipital cortex stimulated. These experiments demonstrated: (1) the consistent shape and position of phosphenes; (2) that increased stimulation pulse duration made phosphenes brighter; and (3) that there was no detectable interaction between neighboring electrodes which were as close as 2.4 mm apart.
As intraocular surgical techniques have advanced, it has become possible to apply stimulation on small groups and even on individual retinal cells to generate focused phosphenes through devices implanted within the eye itself. This has sparked renewed interest in developing methods and apparatuses to aid the visually impaired. Specifically, great effort has been expended in the area of intraocular retinal prosthesis devices in an effort to restore vision in cases where blindness is caused by photoreceptor degenerative retinal diseases such as retinitis pigmentosa and age related macular degeneration which affect millions of people worldwide.
Neural tissue can be artificially stimulated and activated by prosthetic devices that pass pulses of electrical current through electrodes on such a device. The passage of current causes changes in electrical potentials across visual neuronal membranes, which can initiate visual neuron action potentials, which are the means of information transfer in the nervous system.
Based on this mechanism, it is possible to input information into the nervous system by coding the information as a sequence of electrical pulses which are relayed to the nervous system via the prosthetic device. In this way, it is possible to provide artificial sensations including vision.
One typical application of neural tissue stimulation is in the rehabilitation of the blind. Some forms of blindness involve selective loss of the light sensitive transducers of the retina. Other retinal neurons remain viable, however, and may be activated in the manner described above by placement of a prosthetic electrode device on the inner (toward the vitreous) retinal surface (epiretial). This placement must be mechanically stable, minimize the distance between the device electrodes and the visual neurons, and avoid undue compression of the visual neurons.
In 1986, Bullara (U.S. Pat. No. 4,573,481) patented an electrode assembly for surgical implantation on a nerve. The matrix was silicone with embedded iridium electrodes. The assembly fit around a nerve to stimulate it.
Dawson and Radtke stimulated cat's retina by direct electrical stimulation of the retinal ganglion cell layer. These experimenters placed nine and then fourteen electrodes upon the inner retinal layer (i.e., primarily the ganglion cell layer) of two cats. Their experiments suggested that electrical stimulation of the retina with 30 to 100 uA current resulted in visual cortical responses. These experiments were carried out with needle-shaped electrodes that penetrated the surface of the retina (see also U.S. Pat. No. 4,628,933 to Michelson).
The Michelson '933 apparatus includes an array of photosensitive devices on its surface that are connected to a plurality of electrodes positioned on the opposite surface of the device to stimulate the retina. These electrodes are disposed to form an array similar to a “bed of nails” having conductors which impinge directly on the retina to stimulate the retinal cells. U.S. Pat. No. 4,837,049 to Byers describes spike electrodes for neural stimulation. Each spike electrode pierces neural tissue for better electrical contact. U.S. Pat. No. 5,215,088 to Norman describes an array of spike electrodes for cortical stimulation. Each spike pierces cortical tissue for better electrical contact.
The art of implanting an intraocular prosthetic device to electrically stimulate the retina was advanced with the introduction of retinal tacks in retinal surgery. De Juan, et al. at Duke University Eye Center inserted retinal tacks into retinas in an effort to reattach retinas that had detached from the underlying choroid, which is the source of blood supply for the outer retina and thus the photoreceptors. See, e.g., E. de Juan, et al., 99 Am. J. Opthalmol. 272 (1985). These retinal tacks have proved to be biocompatible and remain embedded in the retina, and choroid/sclera, effectively pinning the retina against the choroid and the posterior aspects of the globe. Retinal tacks are one way to attach a retinal array to the retina. U.S. Pat. No. 5,109,844 to de Juan describes a flat electrode array placed against the retina for visual stimulation. U.S. Pat. No. 5,935,155 to Humayun describes a retinal prosthesis for use with the flat retinal array described in de Juan.
Recent attempts to restore vision in the blind have met with extraordinary success. Electrical stimulation of retinas in people with neurodegenerative diseases has demonstrated the potential for direct excitation of neurons as a means of re-establishing sight. Long-term retinal implants in several profoundly blind people were shown to produce perceptions of light and allowed for the detection of motion and discrimination of very simple shapes (Humayun 2003; Humayun et al. 2003). Such achievement brings hope to the millions of people worldwide who suffer from photoreceptor loss due to advanced retinitis pigmentosa or age-related macular degeneration (Heckenlively et al. 1988; Klein et al. 1997). It is expected that ten years from now, macular degeneration will become the single leading cause of legal blindness with an incidence as high as 5.5% in people over 65 (Klein et al. 1997). While degenerative diseases result in severe damage to photoreceptors, inner retinal neurons survive at fairly high rates (Stone et al. 1992; Santos et al. 1997; Kim et al. 2002) and may be electrically excitable. The fundamental concept underlying retinal neuroprosthetic devices is to electrically activate those residual neurons by bypassing the damaged photoreceptors, thus achieving artificial vision in otherwise blind patients. Of several prosthetics designs, epiretinal implants specifically target ganglion cells by positioning electrodes in close proximity to the inner surface of the retina.
In spite of recent successes, the current implants are but a first step toward restoring sight. To create useful vision, stimulating electrodes must be arranged in two-dimensional arrays that generate a visual image made up of a matrix of discrete perceptions of light. Psychophysical studies suggest that foveal implants may provide the user with an acceptable level of mobility if they contain a minimum of about 600 electrodes (Cha et al. 1992a; Cha et al. 1992b). To achieve this number or greater, electrodes must be tightly packed, necessitating small stimulation sites. At present a typical epiretinal implant contains tens of electrodes with diameters of a few hundred μm, spaced several hundred μm apart (Humayun 2003). Considering that such electrodes are much larger than the cells they stimulate, the need for implants with hundreds or thousands of much smaller electrodes is apparent. The success of the next generation of implantable devices will be tied to our understanding of how to activate neurons with extracellular electric stimuli applied to the retinal surface through electrodes that approach cellular dimensions. Little is known about the parameters which would permit reliable retinal stimulation with small electrodes. When the electrode surface area is reduced, current density and charge density increase rapidly, and high charge densities are known to cause tissue damage by electrochemical reactions (Pollen 1977; Brummer et al. 1983; Tehovnik 1996). A detailed in vitro analysis of small electrode stimulation is thus a prerequisite for developing such implants for use in human patients.
A comprehensive literature review reveals that the feasibility of stimulation with arrays of small electrodes in mammalian tissue has not been adequately tested. The majority of studies involving retinal stimulation have used needle-shaped probes with one or two conductors at the end of an insulated rod, such as platinum wires or concentric microelectrodes. In its simplest form, such stimulating probes are made of metal wires several hundred μm in diameter, exposed at the tip and insulated elsewhere (Doty and Grimm 1962; Humayun et al. 1994; Nadig 1999; Weiland et al. 1999; Suzuki et al. 2004).
Others have attempted to utilize stimulating microprobes with tip diameters of 25 μm or smaller (Dawson and Radtke 1977; Wyatt et al. 1994; Rizzo et al. 1997; Jensen et al. 2003). However, the geometry of such probes differs greatly from the planar disk electrode design developed for current epiretinal implants. Stimulation, furthermore, is always limited to a single stimulation site, precluding the study of stimulation using multiple electrodes and their interaction effects. The use of multi-electrode arrays for retinal stimulation has been mainly limited to large electrodes with diameters between 100 and 1500 μm (Greenberg 1998; Humayun et al. 1999; Hesse et al. 2000; Walter and Heimann 2000; Humayun et al. 2003; Rizzo et al. 2003b). Multi-electrode arrays with smaller electrodes (around 10 μm diameter) have been utilized to stimulate the retina in the subretinal space (Zrenner et al. 1999; Stett et al. 2000). Grumet has used an array to selectively stimulate the axons of retinal ganglion cells, using a separate distant array to record somatic spikes (Grumet 1999; Grumet et al. 2000). No study has targeted mammalian ganglion cell bodies for direct epiretinal stimulation using planar electrodes with surface areas below 200 μm2. In this study we establish thresholds for stimulation of ganglion cells in rat, guinea pig, and primate retina using electrodes with surface areas of 30-500 μm2 (diameters of 6-25 μm). We then used these parameters to further investigate frequency dependence, pharmacology, and spatial interaction effects of stimulation. Our arrays use planar disk microelectrodes very similar to those utilized in present epiretinal prosthetics, but smaller by an order or two of magnitude. We conclude our analysis by discussing the results in the context of the pertinent literature. Early and preliminary portions of this work have been presented elsewhere (Sekirnjak et al. 2005).